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The complex distribution of functional groups in carbohydrates, coupled with their strong solvation in water, makes them challenging targets for synthetic receptors. Despite extensive research into various molecular frameworks, most synthetic carbohydrate receptors have exhibited low affinities, and their interactions with sugars in aqueous environments remain poorly understood. In this work, we present a simple pyridinium-based hydrogen-bonding receptor derived from a subtle structural modification of a well-known tetralactam macrocycle. This small structural change resulted in a dramatic enhancement of glucose binding affinity, increasing from 56 M−1 to 3001 M−1. Remarkably, the performance of our synthetic lectin surpasses that of the natural lectin, concanavalin A, by over fivefold. X-ray crystallography of the macrocycle–glucose complex reveals a distinctive hydrogen bonding pattern, which allows for a larger surface overlap between the receptor and glucose, contributing to the enhanced affinity. Furthermore, this receptor possesses allosteric binding sites, which involve chloride binding and trigger receptor aggregation. This unique allosteric process reveals the critical role of structural flexibility in this hydrogen-bonding receptor for the effective recognition of sugars. We also demonstrate the potential of this synthetic lectin as a highly sensitive glucose sensor in aqueous solutions. 

Abstract Achieving selective molecular recognition of hydrophilic anions in water remains a formidable challenge due to the competitive nature of water and the high hydration energies of target anions such as sulfate. Here, we report the design, synthesis, and characterization of a simple dicationic tetralactam macrocycle (BPTL²⁺·2Cl⁻) capable of binding highly hydrated anions in water via charge‐assisted hydrogen bonding. Structural, spectroscopic, thermodynamic, and computational studies reveal that BPTL²⁺ exhibits a strong binding affinity for sulfate (K_a = 2892 M⁻¹), driven primarily by entropic gain from water release and reinforced by electrostatic and hydrogen bonding interactions. Single‐crystal X‐ray diffraction and DFT‐optimized structures confirm the formation of directional [N─H•••O] and [C─H•••O] hydrogen bonds. Comparative studies with a control macrocycle (6Na⁺•HCTL⁶⁻) that has a charge‐neutral binding cavity underscore the essential role of cationic charge in overcoming desolvation enthalpic penalties. The receptor displays anti‐Hofmeister selectivity, preferentially binding more hydrophilic anions. This work provides fundamental insights into the mechanisms of anion recognition in water. It establishes charge‐assisted hydrogen bonding as a powerful strategy for developing next‐generation receptors for sensing, separation, sequestration, transport, and catalysis in aqueous environments.